WDR11-mediated Hedgehog signalling defects underlie a new ciliopathy related to Kallmann syndrome.

Abstract:

:WDR11 has been implicated in congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS), human developmental genetic disorders defined by delayed puberty and infertility. However, WDR11's role in development is poorly understood. Here, we report that WDR11 modulates the Hedgehog (Hh) signalling pathway and is essential for ciliogenesis. Disruption of WDR11 expression in mouse and zebrafish results in phenotypic characteristics associated with defective Hh signalling, accompanied by dysgenesis of ciliated tissues. Wdr11-null mice also exhibit early-onset obesity. We find that WDR11 shuttles from the cilium to the nucleus in response to Hh signalling. WDR11 regulates the proteolytic processing of GLI3 and cooperates with the transcription factor EMX1 in the induction of downstream Hh pathway gene expression and gonadotrophin-releasing hormone production. The CHH/KS-associated human mutations result in loss of function of WDR11. Treatment with the Hh agonist purmorphamine partially rescues the WDR11 haploinsufficiency phenotypes. Our study reveals a novel class of ciliopathy caused by WDR11 mutations and suggests that CHH/KS may be a part of the human ciliopathy spectrum.

journal_name

EMBO Rep

journal_title

EMBO reports

authors

Kim YJ,Osborn DP,Lee JY,Araki M,Araki K,Mohun T,Känsäkoski J,Brandstack N,Kim HT,Miralles F,Kim CH,Brown NA,Kim HG,Martinez-Barbera JP,Ataliotis P,Raivio T,Layman LC,Kim SH

doi

10.15252/embr.201744632

subject

Has Abstract

pub_date

2018-02-01 00:00:00

pages

269-289

issue

2

eissn

1469-221X

issn

1469-3178

pii

embr.201744632

journal_volume

19

pub_type

杂志文章
  • Revisiting the COP9 signalosome as a transcriptional regulator.

    abstract::The COP9 signalosome (CSN) is a highly conserved protein complex that was originally described as a repressor of light-dependent growth and transcription in Arabidopsis. The most studied CSN function is the regulation of protein degradation, which occurs primarily through the removal of the ubiquitin-like modifier Ned...

    journal_title:EMBO reports

    pub_type: 杂志文章,评审

    doi:10.1038/embor.2009.33

    authors: Chamovitz DA

    更新日期:2009-04-01 00:00:00

  • Cytochrome c-d regulates developmental apoptosis in the Drosophila retina.

    abstract::The role of cytochrome c (Cyt c) in caspase activation has largely been established from mammalian cell-culture studies, but much remains to be learned about its physiological relevance in situ. The role of Cyt c in invertebrates has been subject to considerable controversy. The Drosophila genome contains distinct cyt...

    journal_title:EMBO reports

    pub_type: 杂志文章

    doi:10.1038/sj.embor.7400773

    authors: Mendes CS,Arama E,Brown S,Scherr H,Srivastava M,Bergmann A,Steller H,Mollereau B

    更新日期:2006-09-01 00:00:00

  • Oncogenic KRAS signaling activates mTORC1 through COUP-TFII-mediated lactate production.

    abstract::Oncogenic signals contribute to enhanced glycolysis and mTORC1 activity, leading to rapid cell proliferation in cancer. Regulation of glycolysis and mTORC1 by PI3K/Akt signaling is well established, but how KRAS-induced MEK signaling regulates these pathways remains poorly understood. Here, we report a role for MEK-dr...

    journal_title:EMBO reports

    pub_type: 杂志文章

    doi:10.15252/embr.201847451

    authors: Byun JK,Park M,Yun JW,Lee J,Kim JS,Cho SJ,Lee YM,Lee IK,Choi YK,Park KG

    更新日期:2019-06-01 00:00:00

  • Replication-independent chromatin loading of Dnmt1 during G2 and M phases.

    abstract::The major DNA methyltransferase, Dnmt1, associates with DNA replication sites in S phase maintaining the methylation pattern in the newly synthesized strand. In view of the slow kinetics of Dnmt1 in vitro versus the fast progression of the replication fork, we have tested whether Dnmt1 associates with chromatin beyond...

    journal_title:EMBO reports

    pub_type: 杂志文章

    doi:10.1038/sj.embor.7400295

    authors: Easwaran HP,Schermelleh L,Leonhardt H,Cardoso MC

    更新日期:2004-12-01 00:00:00

  • Pharmacological eEF2K activation promotes cell death and inhibits cancer progression.

    abstract::Activation of the elongation factor 2 kinase (eEF2K) leads to the phosphorylation and inhibition of the elongation factor eEF2, reducing mRNA translation rates. Emerging evidence indicates that the regulation of factors involved in protein synthesis may be critical for controlling diverse biological processes includin...

    journal_title:EMBO reports

    pub_type: 杂志文章

    doi:10.15252/embr.201642194

    authors: De Gassart A,Demaria O,Panes R,Zaffalon L,Ryazanov AG,Gilliet M,Martinon F

    更新日期:2016-10-01 00:00:00

  • Codon bias confers stability to human mRNAs.

    abstract::Codon bias has been implicated as one of the major factors contributing to mRNA stability in several model organisms. However, the molecular mechanisms of codon bias on mRNA stability remain unclear in humans. Here, we show that human cells possess a mechanism to modulate RNA stability through a unique codon bias. Bio...

    journal_title:EMBO reports

    pub_type: 杂志文章

    doi:10.15252/embr.201948220

    authors: Hia F,Yang SF,Shichino Y,Yoshinaga M,Murakawa Y,Vandenbon A,Fukao A,Fujiwara T,Landthaler M,Natsume T,Adachi S,Iwasaki S,Takeuchi O

    更新日期:2019-11-05 00:00:00

  • Genome-wide screen identifies a novel p97/CDC-48-dependent pathway regulating ER-stress-induced gene transcription.

    abstract::The accumulation of misfolded proteins in the endoplasmic reticulum (ER) activates the Unfolded Protein Response (UPR(ER)) to restore ER homeostasis. The AAA(+) ATPase p97/CDC-48 plays key roles in ER stress by promoting both ER protein degradation and transcription of UPR(ER) genes. Although the mechanisms associated...

    journal_title:EMBO reports

    pub_type: 杂志文章

    doi:10.15252/embr.201439123

    authors: Marza E,Taouji S,Barroso K,Raymond AA,Guignard L,Bonneu M,Pallares-Lupon N,Dupuy JW,Fernandez-Zapico ME,Rosenbaum J,Palladino F,Dupuy D,Chevet E

    更新日期:2015-03-01 00:00:00

  • Loss of genomic integrity induced by lysosphingolipid imbalance drives ageing in the heart.

    abstract::Cardiac dysfunctions dramatically increase with age. Revealing a currently unknown contributor to cardiac ageing, we report the age-dependent, cardiac-specific accumulation of the lysosphingolipid sphinganine (dihydrosphingosine, DHS) as an evolutionarily conserved hallmark of the aged vertebrate heart. Mechanisticall...

    journal_title:EMBO reports

    pub_type: 杂志文章

    doi:10.15252/embr.201847407

    authors: Ahuja G,Bartsch D,Yao W,Geissen S,Frank S,Aguirre A,Russ N,Messling JE,Dodzian J,Lagerborg KA,Vargas NE,Muck JS,Brodesser S,Baldus S,Sachinidis A,Hescheler J,Dieterich C,Trifunovic A,Papantonis A,Petrascheck M,Kli

    更新日期:2019-04-01 00:00:00

  • Comment on "Close loop peer review" by Michael Hill.

    abstract::Comment on "Close loop peer review" by Michael Hill. ...

    journal_title:EMBO reports

    pub_type: 评论,信件

    doi:10.15252/embr.201948313

    authors: Horowitz A

    更新日期:2019-08-01 00:00:00

  • Toll-like receptor 2-dependent bacterial sensing does not occur via peptidoglycan recognition.

    abstract::Toll-like receptor 2 (TLR2) has been shown to recognize several classes of pathogen-associated molecular patterns including peptidoglycan (PG). However, studies linking PG with TLR2 recognition have relied mainly on the use of commercial Staphylococcus aureus PG and have not addressed TLR2 recognition of other PG type...

    journal_title:EMBO reports

    pub_type: 杂志文章

    doi:10.1038/sj.embor.7400248

    authors: Travassos LH,Girardin SE,Philpott DJ,Blanot D,Nahori MA,Werts C,Boneca IG

    更新日期:2004-10-01 00:00:00

  • Selenoprotein T is a novel OST subunit that regulates UPR signaling and hormone secretion.

    abstract::Selenoprotein T (SelT) is a recently characterized thioredoxin-like protein whose expression is very high during development, but is confined to endocrine tissues in adulthood where its function is unknown. We report here that SelT is required for adaptation to the stressful conditions of high hormone level production...

    journal_title:EMBO reports

    pub_type: 杂志文章

    doi:10.15252/embr.201643504

    authors: Hamieh A,Cartier D,Abid H,Calas A,Burel C,Bucharles C,Jehan C,Grumolato L,Landry M,Lerouge P,Anouar Y,Lihrmann I

    更新日期:2017-11-01 00:00:00

  • Glutamyl-tRNA mediates a switch in RNA polymerase use during chloroplast biogenesis.

    abstract::Chloroplast genes of higher plants are transcribed by two types of RNA polymerase that are encoded by nuclear (NEP (nuclear-encoded plastid RNA polymerase)) or plastid (PEP (plastid-encoded plastid RNA polymerase)) genomes. NEP is largely responsible for the transcription of housekeeping genes during early chloroplast...

    journal_title:EMBO reports

    pub_type: 杂志文章

    doi:10.1038/sj.embor.7400411

    authors: Hanaoka M,Kanamaru K,Fujiwara M,Takahashi H,Tanaka K

    更新日期:2005-06-01 00:00:00

  • Reverse genetics in the mosquito Anopheles gambiae: targeted disruption of the Defensin gene.

    abstract::Anopheles gambiae, the major vector of human malaria parasite, is an important insect model to study vector-parasite interactions. Here, we developed a simple in vivo double-stranded RNA (dsRNA) knockout approach to determine the function of the mosquito antimicrobial peptide gene Defensin. We injected dsRNA into adul...

    journal_title:EMBO reports

    pub_type: 杂志文章

    doi:10.1093/embo-reports/kvf180

    authors: Blandin S,Moita LF,Köcher T,Wilm M,Kafatos FC,Levashina EA

    更新日期:2002-09-01 00:00:00

  • Loss of TMEM106B potentiates lysosomal and FTLD-like pathology in progranulin-deficient mice.

    abstract::Single nucleotide polymorphisms (SNPs) in TMEM106B encoding the lysosomal type II transmembrane protein 106B increase the risk for frontotemporal lobar degeneration (FTLD) of GRN (progranulin gene) mutation carriers. Currently, it is unclear if progranulin (PGRN) and TMEM106B are synergistically linked and if a gain o...

    journal_title:EMBO reports

    pub_type: 杂志文章

    doi:10.15252/embr.202050241

    authors: Werner G,Damme M,Schludi M,Gnörich J,Wind K,Fellerer K,Wefers B,Wurst W,Edbauer D,Brendel M,Haass C,Capell A

    更新日期:2020-10-05 00:00:00

  • The intramembrane protease SPPL2c promotes male germ cell development by cleaving phospholamban.

    abstract::Signal peptide peptidase (SPP) and the four homologous SPP-like (SPPL) proteases constitute a family of intramembrane aspartyl proteases with selectivity for type II-oriented transmembrane segments. Here, we analyse the physiological function of the orphan protease SPPL2c, previously considered to represent a non-expr...

    journal_title:EMBO reports

    pub_type: 杂志文章

    doi:10.15252/embr.201846449

    authors: Niemeyer J,Mentrup T,Heidasch R,Müller SA,Biswas U,Meyer R,Papadopoulou AA,Dederer V,Haug-Kröper M,Adamski V,Lüllmann-Rauch R,Bergmann M,Mayerhofer A,Saftig P,Wennemuth G,Jessberger R,Fluhrer R,Lichtenthaler SF,Lember

    更新日期:2019-03-01 00:00:00

  • Biogenic amine neurotransmitters promote eicosanoid production and protein homeostasis.

    abstract::Metazoans use protein homeostasis (proteostasis) pathways to respond to adverse physiological conditions, changing environment, and aging. The nervous system regulates proteostasis in different tissues, but the mechanism is not understood. Here, we show that Caenorhabditis elegans employs biogenic amine neurotransmitt...

    journal_title:EMBO reports

    pub_type: 杂志文章

    doi:10.15252/embr.202051063

    authors: Joshi KK,Matlack TL,Pyonteck S,Vora M,Menzel R,Rongo C

    更新日期:2021-01-20 00:00:00

  • The FIH hydroxylase is a cellular peroxide sensor that modulates HIF transcriptional activity.

    abstract::Hypoxic and oxidant stresses can coexist in biological systems, and oxidant stress has been proposed to activate hypoxia pathways through the inactivation of the 'oxygen-sensing' hypoxia-inducible factor (HIF) prolyl and asparaginyl hydroxylases. Here, we show that despite reduced sensitivity to cellular hypoxia, the ...

    journal_title:EMBO reports

    pub_type: 杂志文章

    doi:10.1038/embor.2012.9

    authors: Masson N,Singleton RS,Sekirnik R,Trudgian DC,Ambrose LJ,Miranda MX,Tian YM,Kessler BM,Schofield CJ,Ratcliffe PJ

    更新日期:2012-03-01 00:00:00

  • Seaside transportation--from structure to function of translocation machines.

    abstract::The EMBO conference 'From Structure to Function of Translocation Machines' took place in April 2013 in Dubrovnik, Croatia. The meeting brought together a mix of established and aspiring researchers to discuss a wealth of unpublished data and ideas in a lively scientific programme of talks designed to shatter the estab...

    journal_title:EMBO reports

    pub_type:

    doi:10.1038/embor.2013.79

    authors: Lithgow T,Waksman G

    更新日期:2013-07-01 00:00:00

  • AKT isoforms modulate Th1-like Treg generation and function in human autoimmune disease.

    abstract::Foxp3(+) regulatory T cells (Tregs) exhibit plasticity, which dictates their function. Secretion of the inflammatory cytokine IFNγ, together with the acquisition of a T helper 1 (Th1)-like effector phenotype as observed in cancer, infection, and autoimmune diseases, is associated with loss of Treg suppressor function ...

    journal_title:EMBO reports

    pub_type: 杂志文章

    doi:10.15252/embr.201541905

    authors: Kitz A,de Marcken M,Gautron AS,Mitrovic M,Hafler DA,Dominguez-Villar M

    更新日期:2016-08-01 00:00:00

  • ATPase-driven oligomerization of RIG-I on RNA allows optimal activation of type-I interferon.

    abstract::The cytosolic pathogen sensor RIG-I is activated by RNAs with exposed 5'-triphosphate (5'-ppp) and terminal double-stranded structures, such as those that are generated during viral infection. RIG-I has been shown to translocate on dsRNA in an ATP-dependent manner. However, the precise role of the ATPase activity in R...

    journal_title:EMBO reports

    pub_type: 杂志文章

    doi:10.1038/embor.2013.102

    authors: Patel JR,Jain A,Chou YY,Baum A,Ha T,García-Sastre A

    更新日期:2013-09-01 00:00:00

  • Urm1 at the crossroad of modifications. 'Protein Modifications: Beyond the Usual Suspects' Review Series.

    abstract::The ubiquitin-like protein Urm1 can be covalently conjugated to other proteins, such as the yeast thioredoxin peroxidase protein Ahp1p, through a mechanism involving the ubiquitin E1-like enzyme Uba4. Recent findings have revealed a second function of Urm1 as a sulphur carrier in the thiolation of eukaryotic cytoplasm...

    journal_title:EMBO reports

    pub_type: 杂志文章,评审

    doi:10.1038/embor.2008.209

    authors: Pedrioli PG,Leidel S,Hofmann K

    更新日期:2008-12-01 00:00:00

  • The biology of IQGAP proteins: beyond the cytoskeleton.

    abstract::IQGAP scaffold proteins are evolutionarily conserved in eukaryotes and facilitate the formation of complexes that regulate cytoskeletal dynamics, intracellular signaling, and intercellular interactions. Fungal and mammalian IQGAPs are implicated in cytokinesis. IQGAP1, IQGAP2, and IQGAP3 have diverse roles in vertebra...

    journal_title:EMBO reports

    pub_type: 杂志文章,评审

    doi:10.15252/embr.201439834

    authors: Hedman AC,Smith JM,Sacks DB

    更新日期:2015-04-01 00:00:00

  • Critical evaluation of the role of the Toll-like receptor 18-Wheeler in the host defense of Drosophila.

    abstract::Essential aspects of innate immune responses to microbial infections appear to be conserved between insects and mammals. In particular, in both groups, transmembrane receptors of the Toll superfamily play a crucial role in activating immune defenses. The Drosophila Toll family member 18-Wheeler had been proposed to se...

    journal_title:EMBO reports

    pub_type: 杂志文章

    doi:10.1093/embo-reports/kvf130

    authors: Ligoxygakis P,Bulet P,Reichhart JM

    更新日期:2002-07-01 00:00:00

  • Distinct but overlapping domains of AKAP95 are implicated in chromosome condensation and condensin targeting.

    abstract::A-kinase (or PKA)-anchoring protein AKAP95 is a zinc-finger protein implicated in mitotic chromosome condensation by acting as a targeting molecule for the condensin complex. We have identified determinants of chromatin-binding, condensin-targeting and chromosome-condensation activities of AKAP95. Binding of AKAP95 to...

    journal_title:EMBO reports

    pub_type: 杂志文章

    doi:10.1093/embo-reports/kvf089

    authors: Eide T,Carlson C,Taskén KA,Hirano T,Taskén K,Collas P

    更新日期:2002-05-01 00:00:00

  • Redox activation of ATM enhances GSNOR translation to sustain mitophagy and tolerance to oxidative stress.

    abstract::The denitrosylase S-nitrosoglutathione reductase (GSNOR) has been suggested to sustain mitochondrial removal by autophagy (mitophagy), functionally linking S-nitrosylation to cell senescence and aging. In this study, we provide evidence that GSNOR is induced at the translational level in response to hydrogen peroxide ...

    journal_title:EMBO reports

    pub_type: 杂志文章

    doi:10.15252/embr.202050500

    authors: Cirotti C,Rizza S,Giglio P,Poerio N,Allega MF,Claps G,Pecorari C,Lee JH,Benassi B,Barilà D,Robert C,Stamler JS,Cecconi F,Fraziano M,Paull TT,Filomeni G

    更新日期:2020-11-27 00:00:00

  • Extracellular vesicles deliver Mycobacterium RNA to promote host immunity and bacterial killing.

    abstract::Extracellular vesicles (EVs) have been shown to carry microbial components and function in the host defense against infections. In this study, we demonstrate that Mycobacterium tuberculosis (M.tb) RNA is delivered into macrophage-derived EVs through an M.tb SecA2-dependent pathway and that EVs released from M.tb-infec...

    journal_title:EMBO reports

    pub_type: 杂志文章

    doi:10.15252/embr.201846613

    authors: Cheng Y,Schorey JS

    更新日期:2019-03-01 00:00:00

  • Single-cell transcriptomics reveals distinct inflammation-induced microglia signatures.

    abstract::Microglia are specialized parenchymal-resident phagocytes of the central nervous system (CNS) that actively support, defend and modulate the neural environment. Dysfunctional microglial responses are thought to worsen CNS diseases; nevertheless, their impact during neuroinflammatory processes remains largely obscure. ...

    journal_title:EMBO reports

    pub_type: 杂志文章

    doi:10.15252/embr.201846171

    authors: Sousa C,Golebiewska A,Poovathingal SK,Kaoma T,Pires-Afonso Y,Martina S,Coowar D,Azuaje F,Skupin A,Balling R,Biber K,Niclou SP,Michelucci A

    更新日期:2018-11-01 00:00:00

  • Estrogen receptors: orchestrators of pleiotropic cellular responses.

    abstract::Estrogen receptors (ERs) orchestrate both transcriptional and non-genomic functions in response to estrogens, xenoestrogens and signals emanating from growth factor signalling pathways. The pleiotropic and tissue-specific effects of estrogens are likely to be mediated by the differential expression of distinct estroge...

    journal_title:EMBO reports

    pub_type: 杂志文章,评审

    doi:10.1093/embo-reports/kve185

    authors: Moggs JG,Orphanides G

    更新日期:2001-09-01 00:00:00

  • DNA polymerases and somatic hypermutation of immunoglobulin genes.

    abstract::Somatic hypermutation of immunoglobulin variable genes, which increases antibody diversity, is initiated by the activation-induced cytosine deaminase (AID) protein. The current DNA-deamination model posits that AID deaminates cytosine to uracil in DNA, and that mutations are generated by DNA polymerases during replica...

    journal_title:EMBO reports

    pub_type: 杂志文章,评审

    doi:10.1038/sj.embor.7400582

    authors: Seki M,Gearhart PJ,Wood RD

    更新日期:2005-12-01 00:00:00

  • Nanoscale spatial induction of ultraviolet photoproducts in cellular DNA by three-photon near-infrared absorption.

    abstract::The high-resolution spatial induction of ultraviolet (UV) photoproducts in mammalian cellular DNA is a goal of many scientists who study UV damage and repair. Here we describe how UV photoproducts can be induced in cellular DNA within nanometre dimensions by near-diffraction-limited 750 nm infrared laser radiation. Th...

    journal_title:EMBO reports

    pub_type: 杂志文章

    doi:10.1038/sj.embor.7400028

    authors: Meldrum RA,Botchway SW,Wharton CW,Hirst GJ

    更新日期:2003-12-01 00:00:00